Novel pharmacotherapeutic approaches for Parkinson's Disease (PD) are needed. Current long term dopamine replacement therapies result in dyskinesias and other debilitating side effects. Surgical treatments are efficient but they are invasive, costly, and suitable only for a specific subset of patients. New, non- dopaminergic pharmacological treatments for PD that could reduce or replace the use of dopaminergic drugs, thereby delaying, reducing, or even preventing dyskinesias and other side-effects, could therefore have a significant impact on the quality of life of PD patients. One receptor that has come to light as a possible target for such a non-dopaminergic treatment is the metabotropic glutamate receptor subtype 5 (mGluR5). Hyperactive glutamatergic neurotransmission is an important physiological feature of PD, especially at subthalamofugal and corticostriatal synapses. Antagonists at ionotropic glutamate receptors have shown antiparkinsonian effects, but are unsuitable as a PD therapy because of the serious side effects they cause. So, attention has been turned to metabotropic glutamate receptors. mGluR5 antagonists have been shown to have antiparkinsonian effects in rodent models of PD, and our preliminary data show a similar effect in MPTP-treated monkeys. Another potential non-dopaminergic anti-PD drug target is the adenosine A2A receptor (A2AR). A2AR is expressed almost exclusively in striatal medium spiny neurons of the indirect pathway. Antagonists of A2AR have antiparkinsonian effects in rodent and primate models of PD. One A2AR antagonist is currently in clinical trials and has shown limited efficacy in humans. The drug is able to potentiate the effect of L-Dopa and decreases time spent in the "off state." However, the drug has been unable to significantly improve dyskinesia or parkinsonism scores, leaving much room for improvement. In rodents, simultaneous administration of A2AR and mGluR5 antagonists has a synergistic antiparkinsonian effect. In this proposal, we will test the acute and chronic efficacy of this antagonist combination treatment in the gold-standard model of PD, the MPTP-treated monkey. In order to determine whether the indirect pathway is involved in the antiparkinsonian mechanism of action of this treatment, we will inject one or both of the drugs directly into the striatum or GPe. This research is relevant to public health because there are over 50,000 new diagnoses of Parkinson's Disease each year in the United States alone. So, an effective symptomatic treatment for PD that does not induce serious side effects could improve the quality of life of many thousands of PD patients worldwide.